Autoimmune disease results from the escape of (er defects In) normal control mechanisms and developmental pathways that maintain a healthy immune system. Despite the increase in autoimmune disease within our aging population, the mechanisms by which autoimmune cells are generated and how these cells are programmed are not well understood. We hypothesize that these abnormal events and programming are in part controlled by a unique epigenetic program that will be revealed in the DNA methylation and histone modification landscape that Is established within the genomes of autoimmune cells. Systemic lupus erythematosus (SLE) patients undergo relapsing episodes of disease. During autoimmune flares, specific B cell subsets dominate that are likely responsible for the disease flares. Aside from surface marker phenotyping, little Is known about the molecular programming and potential of these autoimmune B cells. As part of the Emory ACE, we will use whole genome strategies to derive and Integrate epigenetic and transcription profiles for autoimmune B cells purified frem SLE patients and determine the epigenetic landscape and programming of these cells and hew they are different from the B cells of healthy individuals. Preliminary data have identified candidate loci, including cell surface markers that are both differentially expressed and epigenetically regulated in SLE patient derived B cells. We will also follow SLE patients on Belimumab (anti-BAFF/BLyS) and Rituximab (Anti-CD20) to gain insight into how the B cell subsets and their epigenetic and transcriptional programming change following treatment. For the Collaborative Project, we hypothesize that epigenetic determinants for both B and T cells will play a role in etiology or sustainment of other autoimmune diseases. With this overall hypothesis in mind, we propose to collaborate with other centers to determine the transcriptomes and epigenomes of autoimmune and healthy control B and T cells that are the focus of their investigations. Because the technology and approaches are universal, this program is ideally suited for a collaborative program. We expect that the integration of our combined studies will provide insight into the development of autoimmunity, cellular programming, and immune dysfunction, and will identify biomarkers that could be used for diagnosis, monitoring disease progression, or as targets for novel therapies.